FACTORS  IN  ENDOGENOUS  URIC  ACID 
METABOLISM 


RALPH  CONNER  CORLEY 

A.  B.  University  of  Illinois,  1921 


THESIS 

SUBMITTED  IN  PARTIAL  FULFILLMENT  OF  THE  REQUIREMENTS 
FOR  THE  DEGREE  OF  MASTER  OF  ARTS  IN  CHEMISTRY 
IN  THE  GRADUATE  SCHOOL  OF  THE  UNIVERSITY 
OF  ILLINOIS,  1922 


URBANA,  ILLINOIS 


. 


. 


UNIVERSITY  OF  ILLINOIS 


THE  GRADUATE  SCHOOL 


May  24 


1 HEREBY  RECOMMEND  THAT  THE  THESIS  PREPARED  UNDER  MY 


SUPERVISION  BY  RALPH 


■COLLEY. 


ENTITLED. 


ACIQRS-I3L 


ENDOGEIJOUS 


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THE  DEGREE  OF Master  of  Arts  in  Ch^istry 


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^k*er> 


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Committee 

on 

Final  Examination* 


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S9i  ' 


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TABLE  0 S CONTENTS 

I  INTRODUCTION • 

II  HISTORICAL  ................ 

Ill  EXPERIMENTAL  * ......... 

A.  Methods  ............... 

E.  Controls.  .............. 

C.  Effect  of  Glyeocoll  

D.  Influence  of  Eat.  . . . 

E.  Fat  and  Gly  cocoll  . 

F.  Glycerol 

G.  Honey.  ......  

H.  Karo  Corn  Syrup  ........... 

I.  Cystine.  . 

IV  GENERAL  DISCUSSION  OF  RESULTS,  ...... 

V  SUMMARY  

' VI  BIBLIOGRAPHY  . . 


1 

2 

7 

7 

8 

8 

9 

10 

10 

11 

12 

13 

14 

57 

28 


I wish  to  express  rny  sincere  gratitude 
and  appreciation  to  Dr.  Howard  3.  Lewis  for 
his  constant  assistance  and  inspiration  dur- 
ing the  course  of  these  experiments. 


I INTRODUCTION 


The  question  of  general  metabolism  is  intimately  bound  up 
with  the  question  of  endogenous  uric  acid  metabolism*  This  is 
a logical  corollary  of  the  facts  that  tissue  metabolism  is  in- 
herently cellular,  and  cellular  activity  has  as  one  important 
factor  nuclear  metabolism.  Furthermore  in  the  final  analysis, 
the  elimination  of  endogenous  uric  acid  is  an  index  of  the 
breakdown  of  nuclear  material.  With  these  facts  in  mind,  it  is 
apparent  that  advances  in  the  theory  of  nuclear  metabolism  must 
of  a necessity  afford  a firmer  foundation  for  the  development 
of  our  theories  of  general  metabolism.  It  is  therefore  deemed 
advisable  to  consider  all  aspects  of  this  general  problem.  The 
relation  of  protein  and  protein  derivatives  in  the  diet  on  en- 
dogenous uric  acid  excretion  has  been  rather  thoroughly  inves- 
tigated. The  purpose  of  the  present  paper  is  to  report  inves- 
tigations in  regard  to  the  effect  of  other  types  of  food-stuffs, 
particularly  fats  and  carbohydrates  upon  endogenous  uric  acid 


metabolism 


II  HISTORICAL 

Uric  acid  has  been  a well  recognized  constituent  of  the 
urine  for  nearly  a century  and  a half  since  Scheele(l)  isolated 
it  from  urine  and  urinary  calculi.  Some  hundred  years  later, 
the  correlation  of  gout  with  uric  acid  was  established  by 
Pearson(2  ),  It  remained,  however,  for  Kossel  (3)  to  lay  the 
foundation  stores  of  present  uric  acid  theories  by  demonstrat- 
ing the  relation  of  uric  acid,  and  other  purines  to  nuclear 
metabolism. 

Burian  and  Schur(4)  were  the  first  to  clearly  distinguish 
the  two  kinds  of  urinary  uric  acid  as  differentiated  by  origin- 
exogenous,  that  derived  directly  from  preformed  purine  precursors 
in  the  diet  and  endogenous,  that  resulting  from  the  vital  pro- 
cesses of  the  cell.  Thus  according  to  the  definitions  now  ac- 

acid 

cepted  exogenous  uric  acid  is  that  fraction  of  the  uric /of  the 

not  1 

urine  which  has/  been  a part  of  the  living  cells  or  tissues  of 
the  organism,  while  the  endogenous  factor  is  a product  of  the 
activity  of  the  cell  and  has  been  formed  from  an  actual  consti- 
tuent of  the  protoplasm.  Burian  and  Schur  concluded  that  the 
endogenous  portion  of  the  uric  acid  eliminated  was  constant  and 
independent  of  the  diet.  Burian  believed  that  endogenous  uric 
acid  was  formed  principally  from  the  hypoxan.thine  of  inosinic 
ae i i , one  oi  the  mononucleotides  found  only  in  muscle  tissue. 

In  accord  with  this  theory  he  believed  that  muscular  work  would 
increase  trie  endogenous  uric  acid.  Siven(5)  repeated  various 


-3- 


acid 

phases  of  Burian*s  work,  and  while  he  found  that  the  uric/  elimi- 
nation was  greater  during  working  than  sleeping  hours,  in  general 
he  failed  to  confirm  the  view  of  Burian  that  muscular  work  in- 
creased the  uric  acid  output. 

On  the  other  hand,  Mares(6)  was  of  the  opinion  that  some  or 
possibly  all  of  this  excreted  uric  acid  resulted  from  glandular 
activity,  particularly  that  of  the  digestive  glands.  In  support 
of  his  idea,  he  showed  that  the  ingestion  of  food  free  from  pre- 
formed purines  caused  a marked  increase  in  the  amount  of  uric 
acid  eliminated.  He  argued  therefore  that  the  observed  increase 
resulted  from  the  disintegration  of  nuclear  material  in  the 
glands  of  the  alimentary  tract,  as  a result  of  the  work  imposed 
on  them  during  the  process  of  digestion. 

Smetanka( 7 ) confirmed  Mares  results,  but  was  forced  to  make 
an  extension  of  Mares  theory  since  he  found  that  honey,  a food 
requiring  very  little  digestion  since  it  is  essentially  invert 
sugar,  a mixture  of  the  two  mono-saccharides,  glucose  and  fruc- 
tose, also  increases  the  uric  acid  excretion.  He  interpreted 
his  results  to  indicate  that  uric  acid  was  formed  as  a result  of 
trie  increased  breakdown  of  nuclear  material  during  the  period  of 
the  exaggerated  glycogenetic  activity  of  the  liver. 

Mendel  and  Stehle(8)  came  to  the  conclusion  that  a part  at 
least  of  the  endogenous  uric  acid  originated  from  the  activity 
of  the  alimentary  canal.  The  striking  part  of  their  experiment 
was  that  pilocarpine  a drug  stimulating  glandular  secretion  in- 
creased the  excretion  of  uric  acid,  while  atropine  an  inhibitor 


\ 


l . ..  - X 


* / - 


-4- 


of  glandular  activity  caused  a decrease  in  the  output  of  uric 
acid.  However,  they  found  that  the  mechanical  work  of  the  di- 
gestive tract  caused  by  the  administrat ion  of  bulky  food  or  lax- 
atives was  not  a factor  in  the  stimulation  of  uric  acid  output. 

Considerable  work  has  been  done  on  this  problem  and  various 
theories  have  been  advanced  to  explain  the  observed  phenomena. 
The  simplest  way  to  get  a view  of  the  entire  problem  and  the  ad- 
vances that  have  been  made,  is  probably  to  give  a brief  recapi- 
tulation 14)  of  the  most  important  theories  which  have  been  sug- 
gested from  time  to  time.  Thus  the  increase  of  uric  acid  elimi- 
nation following  the  ingestion  of  purine  free  foods  have  been 
attributed  in  general  to  the  following  factors,  (a)  Nuclear 
disintegration  in  the  glands  of  the  alimentary  canal  occasioned 
by  the  work  of  digestion(  6 ), ( 7 ),  ( 8 ).  (b)  Nuclear  disintegration 

associated  with  the  work  of  digestion  and  food  storage(7).  (c) 
Synthesis  of  purines  from  carbohydrates^ 9 ).  (d)  Synthesis  of 

purines  from  arginine  and  histidine( 10  ), ( 11 ).  (e)  Stimulation 

of  the  process  of  elimination  which  was  suggested  by  Lewis,  Dunn 
and  Doisy  (12),  but  regarded  by  them  as  untenable,  (f)  General 
stimulation  of  cellular  metabolism  by  amino  acids  or  their  cata- 
bolic derivative(  12  ). 

The  objection  to  the  theories  of  Mares  and  Sme tanka  is  that 
it  is  scarcely  conceivable  that  nuclear  disintegration  of  the 
tissues  of  the  digestive  apparatus  or  liver  would  be  sufficient- 
ly extensive  to  account  for  the  relatively  large  increases  in 
uric  acid  elimination.  It  is  of  course  quite  conceivable  that 
a part  at  least  of  the  uric  acid  has  this  origin  but  such/theory 


_c,  _ 


does  not  account  at  all  for  the  marked  effect  of  amino-acids, 
which  probably  do  not  affect  to  any  marked  extent  the  digestive 
apparatus  in  the  process  of  their  digestion. 

The  chief  advocates  of  the  formation  of  purines  from  carbo- 
hydrates are  Graham  and  Poulton(9).  As  one  support  of  their 
theory  they  point  to  the  conclusions  of  Enoop  and  V/indaus(  13  ) 
who  found  that  when  glucose  is  exposed  to  the  action  of  sunlight 
and  the  highly  dissociated  compound  Zn(  OH  )a  .4NH3,  methyl  glyoxal 
and  9-methyl  imidazol  are  formed.  Notwithstanding  these  interest- 
ing experiments  conducted  invitro  it  scarcely  seems  probable 
that  carbohydrates  are  concerned  with  the  synthesis  of  uric  acid 
or  other  purines. 

Ackeroyd  and  Hopkins(lO)  found  a decrease  in  allant 0 in  ex“ 
cretion  when  young  rats  were  fed  diets  free  of  arginine  and  his- 
tidine. Harding  and  Young(ll)  came  to  similar  conclusions  when 
they  observed  that  the  feeding  of  placenta,  which  has  a high 
content  of  arginine  causes  more  of  an  increase  in  allantoin  ex- 
cretion than  does  an  equal  amount  of  muscle  tissue.  On  the  con- 
trary, other  authors( 19 ) have  been  unable  to  show  any  relation- 
ship between  the  arginine  and  histidine  contant  of  the  diet  and 
the  uric  acid  or  allantoin  output  of  the  urine. 

While  the  data  in  regard  to  the  relation  suggested  between 
uric  acid  and  arginine  and  histidine  seem  at  first  thought  quite 
contradictory,  as  Rose(14)  points  out  in  a recent  paper,  it  is 
possible  to  consider  these  mutually  supplementory , the  differences 
being  due  to  quantitative  considerations  in  the  living  body. 


-6- 


Further  work  oil  this  subject  will  be  quite  valuable,  if  it  can 
clear  up  the  problem  or  at  any  rate  point  to  a means  for  its 
solution. 

The  most  recent  theory  and  seemingly  the  most  adequate  is 
that  presented  by  Lewis,  Dunn  and  Doisy(12)»  According  to  this 
conception  increases  in  uric  acid  elimination  following  inges- 
tion of  purinee-free  protein  or  amino-acids  are  due  to  a general 
cellular  stimulation,  caused  by  the  amino-acids  or  some  of  their 
catabolic  derivatives. 

Following  quite  different  methods  and  experimental  techni- 
que, Hose  was  led  to  the  same  conclusion  as  that  expressed  by 
Lewis  and  collaborators.  He,  however,  extended  the  theory  and 
decided  that  the  increases  following  ingestion  of  other  food- 
stuffs or  chemical  substances  is  due  xo  a general  stimulating 
action  upon  cellular  metabolism  caused  by  digestive  or  metabol- 
ic products  of  such  foods  or  chemical  substances.. 

In  order  to  put  this  theory  on  a firmer  basis  and  to  see 
whether  it  is  generally  applicable  it  was  deemed  advisable  to 
extend  the  work  of  Lewis  and  collaborators  to  the  other  types 
of  food  stuffs,  fats  and  carbohydrates  and  to  their  cleavage 
products  as  far  as  possible.  This  phase  of  the  work  has  formed 
the  subject  of  the  present  invest igat ion. 


III  EXPERIMENTAL 
Methods 

Uric  acid  was  determined  colorimetrieally  by  the  Benedict 
and  Hitchcock  modification  of  the  Eolin-Macfcllum  **DenA$  method. 
Creatinine  was  determined  by  Polin' s colorimetric  method. 

The  subject  of  these  experiments  was  a healthy  young  mail, 
aged  21  years,  with  a weight  of  about  67  kilos.  The  experiments 
were  usually  conducted  on  Wednesday7,  and  Eriday.  Prom  Monday  even- 
ing until  the  conclusion  of  the  experiment  Eriday,  a diet  practi- 
cally free  of  purines  and  low  in  protein  was  consumed.  During 
the  experimental  days  no  food  was  eaten  after  6: 00  P.M.  the  pre- 
ceding day,  at  which  time  a light  meal  only  was  consumed,  until 
the  completion  of  the  experiment  or  experiments.  Later  in  the 
course  of  the  experiments,  two  were  run  on  succeeding  days  usually 
Tuesday  and  Wednesday,  the  same  general  dietary  regulations  being 
observed. 

As  in  other  similar  experiments  conducted  in  this  labora- 
tory(15)  200  ec.  of  water  were  ingested  hourly,  to  insure  that 
the  volumes  of  the  urine  collected  be  large  enough  to  minimize 
erros  due  to  manipulation  or  incomplete  emptying  of  the  bladder* 
Since  the  excretion  of  creatinine  tends  to  remain  constant  from 
hout  to  hour,  and  is  not  influenced  by  the  diet,  if  creatinine 
free,  this  constituent  of  the  urine  was  also  determined  to  give 
an  index  of  the  completeness  of  the  collection  of  urine. 


-8- 


Controls 

In  order  to  interpret  the  significance  of  changes  in  uric 
acid  excretion  following  ingestion  of  various  food—  stuffs  and 
other  substances,  it  is  necessary  to  have  accurate  information 
concerning  the  degree  and  kind  of  variations  to  be  expected  in 
the  fasting  subject  normally.  Control  experiments,  in  which  no 
food  at  all  was  eaten  during  the  course  of  the  experiments,  were 
carried  out  and  repeated  at  frequent  intervals,  in  order  to  de- 
termine whether  or  not  the  level  of  endogenous  uric  acid  metabolr* 
ism  was  altered  by  such  experiments  as  these. 

As  has  already  been  observed  by  Mendel  and  Stehle(8)  and 
Heuwirth( 15  ) and  others  in  this  laboratory,  there  is  a tendency 
for  the  uric  acid  elimination  to  decrease  steadily  during  the 
day.  The  hourly  variations  observed  were  much  less  marked  than 
some  other  investigators  have  reported(  14  ),  (15).  Since  under 
the  control  conditions  the  elimination  of  uric  acid  is  subject 
to  a stead}?-  decrease,  the  assumption  seems  warranted  that  aiiy 
marked  rise  in  the  level  of  excretion,  particularly  during  the 
later  morning  hours,  is  caused  by  the  substances  ingested. 

Effect  of  Glycocoll 

It  has  already  been  shown  in  this  laboratory  that  the  inges- 
tion of  amino  acids  causes  a marked  rise  in  the  endogenous  uric 
acid  excretion.  In  order,  therefore,  to  get  a comparison  of  the 
relative  increases  caused  by  amino  acids  and  the  other  food  stuffs 
to  be  studied,  it  was  considered  advisable  to  repeat  the  experi- 
ments with  glycocol  (Table  II).  This  experiment  served  also  to 


-9- 


determine  whether  the  reaction  of  this  subject  to  amino  acids 
was  similar  to  that  which  has  been  observed  in  other  individu- 
als^ ).  It  will  be  noted  from  the  table  that  there  is  a quite 
apparent  rise  the  first  hour  following  administrat ion,  with  the 
maximum  effect  the  second  and  third  hours*  The  effect  has 
scarcely  disappeared  by  the  fifth  hour,  when  the  experiment  con- 
c luded.. 

Influence  of  Pat. 

Practicall3r  all  the  available  work  done  on  the  effect  of 

fat  on  the  uric  acid  excretion  seems  subject  to  the  objection 

t nan 

that  it  has  been  conducted  on  a daily  rather /on  an  hour ly  basis, 
and  furthermore  that  other  food-stuffs  have  been  present  in  the 
diets  studied. 

Hermann  (16)  and  Horbaczewski  and  Kenera( 17  ) reported  a di- 
minished uric  acid  excretion  following  the  consumption  of  butter 
(100  g daily).  Umeda( 18  ) likewise  found  that  the  uric  acid  ex- 
cretion was  diminished  on  a fat-rich  carbohydrate-poor  diet. 

Mendel  and  Stehle  in  a study  of  hourly  elimination  found 
that  the  eating  of  butter  caused  no  apparent  change  in  the  uric 
acid  excretion. 

Table  III  presents  the  results  obtained  with  butter  and 
cream.  Neither  cause  any  apparent  change  in  uric  acid  output 
which  was  quite  similar  to  that  obtained  during  the  fasting  con- 
trols. Since  it  is  well  known  that  fat  is  relatively  slow ly  di- 
gested and  absorbed,  it  seemed  advisable  to  continue  the  experi- 
ments for  a larger  period  of  time  in  order  to  afford  time  for 


. - i ^ 


^ i - 


-10- 


the  fat  to  be  digested  and  absorbed,  so  that  it  might  exert 
any  possible  metabolic  influence.  For  this  reason  experiment 
14  was  run  six  hours,  and  experiment  25  was  run  seven  hours 
after  drinking  the  cream*  During  this  time  which  seems  extend- 
ed enough  for  the  complete  absorption  of  the  fat  no  effect  on 
the  uric  acid  elimination  was  detected. 

Fat  Followed  by  Glycocoll Ingestion. 

In  view  of  the  experiments  just  considered  (Table  IV)  it 
was  deemed  interesting  to  determine  whether  the  previous  feed- 
ing of  fat  would  in  any  w^ay  interfere  with  the  stimulating  ac- 
tion of  amiiio-acids  on  the  uric  acid  excretion.  For  this  pur- 
pose the  consumption  of  cream  was  followed  by  the  ingestion  of 
glycoccl  (10  g)  three  hours  later.  In  confirmation  of  other 
experiments  there  was  at  first  a steady  fall  in  the  uric  acid 
output.  However,  under  the  influence  of  the  glycocol  there 
was  a marked  increase  in  the  uric  acid  elimination,  the  second 
hour  after.  It  is  of  course  noted  that  at  this  time  of  day 
the  general  level  of  excretion  is  already  lower  so  that  the 
absolute  rise  is  not  so  marked  as  in  the  experiment  conducted 
earlier  in  the  day.  The  relative  increase  is  however  quite 
marked. 

Glycerol 

Horbaczewski  and  Kanera(17)  and  Umeda(  18  ) found  that  the 
ingestion  of  glycerol  caused  a noticeable  increase  in  uric  acid 
elimination*  These  writers  noted  that  while  free  glycerol 

caused  an  increase,  glycerol  combined  in  the  fat  molecule 


-11- 


caused  no  such  effect. 

Results  in  accord  with  those  of  earlier  workers  are  re- 
corded (Table  V).  The  ingestion  of  5°  S °f  glycerol  caused  in 
each  case  a marked  rise  in  uric  acid  output.  10  g had  no  ap- 
parent effect ♦ 

Influence  of  Honey 

Smetanka  found  that  the  ingestion  of  honey  (200  g)  caused 
an  increase  in  uric  acid  excretion.  It  was  on  the  strength  of 
these  results  that  he  advanced  his  theory  that  the  disintegra- 
tion of  not  only  the  cells  of  the  digestive  tract,  cut  also  of 
the  liver  during  glycogenetic  activity  was  responsible  for  the 
observed  increases  in  uric  acid  elimination.  He  came  to  this 
conclusion  since  the  digestion  of  honey  imposes  very  little 
work  on  the  alimentary  canal. 

In  connection  with  Smetanka* s work  concerning  the  effect 
of  honey,  the  investigations  of  Graham  and  Poulton  and  of 
Umeda  are  of  interest.  These  authors  believe  that  a part  of 
the  endogenous  uric  acid  may  arise  through  synthesis  from  carbo- 
hydrates. The  observation  of  Knoop  and  Windaus  in  regard  to 
invitro  synthesis  of  purines  has  already  been  cited. 

In  Table  VI  are  given  the  results  of  7 exp erimeiits  in  re- 
gard to  the  effect  of  honey.  All  of  the  experiments  show'  a 
marked  rise  in  the  excretion  of  uric  acid.  The  hourly  samples 
of  urine  were  tested  for  sugar,  using  Benedict’s  solution. 

There  was  no  apparent  correlation,  however  between  glycosuria 
and  uric  acid  level,  since  at  times  the  test  was  positive  and 


-12- 


in  another  similar  experiment  the  test  would  be  negative.  Thus 
one  sample  of  urine  contained  sugar  when  110  g of  honey  was 
taken  while  in  several  experiments  there  was  no  glycosuria  fol- 
lowing  the  ingestion  of  200  g of  honey. 


Effect  of  Karo  Corn  Syrup. 

As  has  already  been  alluded  to  carbohydrates  ri-ch  diets 
seem  to  cause  an  increase  in  endogenous  uric  acid.  In  Table 


VII  are  given  the  results  of  experiments  in  regard  to  the  effect 
of  Karo  cane-syrup  on  the  uric  acid  excretion.  It  will  be  seen 


that  in  general  the  ingestion  of  smaller  amounts  than  200  g show 
no  efiect,  those  above  200  g consistently  show  an  increase  in 
txie  uric  acid  elimination  while  those  in  the  neighborhood  of 
200  g show  some  positive  and  some  negative  results* 

The  conclusion  seems  inevitable  therefore  that  there  is  a 


quantitative  relationship  between  the  amount  of  glucose  ingested 
and  tne  effect  produced.  For  the  subject  of  these  experiments 
it  seems  that  2 00  g my  be  taken  as  the  critical  point.  If  less 

than  thls  amount  was  taken  there  was  no  effect,  while  more  than 
this  amount  gives  a decided  effect. 


oince  honey  is  essentially  invert  sugar 

and 

cose  and  fructose, /the  the  sugar  of  the  Karo 

, . , , . 1 /is  glucose 

dicat ed  oy  analysis  /it  wrould  be  interesting 

effect  fructose  alone  would  have.  The  cost 


, a mixture  of  glu- 
corn  s3/rup,  as  in- 
to determine  what 
of  the  pure  fructos 


e 


prevented  such  experiments  being  conducted. 

1.  Analysis  of  Corn  Syrup.  Sherman’s  food  Products,  Hew 'fork 
-ater  19.0  per  cent  Dextrine  42.0  per  cent 

Glucose  38. 5 per  cent  Ash  0.5  per  cent 


I 


-13- 


Cystine 

Table  VIII  gives  the  results  of  one  experiment  involving 
the  ingestion  of  5 g of  cystine.  The  difficulty  of  taking  the 
cystine  into  solution  prevented  a repetition  of  this  experiment. 
A solution  acid  enough  to  hold  the  cystine  in  solution  was  too 
strongly  acidic  to  be  swallowed.  Several  attempts  to  do  so  pro- 
duced a mild  nausea. 

3 g gave  little  effect  and  yet  it  seems  that  there  is  an 
actual  ris,e  in  the  uric  acid  excretion. 


—14— 


IV  GENERAL  DISCUSSION  OF  RESULTS 


It  has  been  well  established  that  the  endogenous  uric  acid 
excreted  is  not  independent  of  the  diet,  and  furthermore  that 
purine  free  proteins  cause  a marked  use  in  the  excretion  oi 
uric  acid.  More  recent  work,  particularly  from  this  laboratory,] 
has  shown  that  amino  acids  have  the  same  marked  effect  as  pro- 
teins themselves.  These  reults  have  been  interpreted  as  indi- 
cating that  the  increase  in  uric  acid  elimination  is  due  to  a 
general  stimulation  of  cellular  or  nuclear  catabolism,  by  the 
amino  acids  or  some  of  their  catabolic  products. 

It,  however,  has  been  observed  frequently  that  proteins 
and  protein  derivatives  are  not  unique  in  their  stimulation  of 
uric  acid  metabolism,  but  that  various  other  types  of  substances] 
give  rise  to  the  same  phenomena. 

The  results  presented  in  this  paper  are  quite  in  accord 
with  most  other  work  that  has  been  done  on  this  subject.  Vari- 
ous invest igators  to  be  sure  have  found  that  a fat -rich  carbo- 
hydrate poor  diet  causes  a decrease,  while  the  results  present- 
ed in  the  present  paper  indicate  that  the  ingestion  of  fat 
causes  no  apparent  effect  oxi  the  uric  acid  excretion,  however, 
these  results  are  not  entirely  contradictory  for  the  work  was 
carried  out  under  slightly  different  conditions,  inasmuch  as  in 
the  experiments  cited,  the  effect  of  the  fat  alone  was  not  de- 
termined and  the  results  are  merely  the  effect  of  the  fat  in 
conjunction  with  other  types  of  foodstuffs. 


-15- 

At  first  thought  it  seems  peculiar  that  free  glycerol 
causes  a marked  effect  while  glycerol  combined  in  the  fat  mole- 
cule seems  to  exert  little  influence.  However,  much  less  glycer- 
ol was  ingested  in  the  form  of  fat  than  when  it  was  ingested 
alone.  Besides  it  is  necessary  to  consider  the  time  relations 
that  obtain.  Glycerol  is  quite  soluble  so  that  it  should  be 
absorbed  immediately  while  it  is  well  known  that  the  digestion 
of  fat  proceeds  at  a comparatively  slow  rate  with  a consequently 
slow  liberation  of  glycerol. 

In  general  it  seems  as  if  the  effect  produced  by  these  var- 
ious non-protein  foodstuffs  is  dependent  on  the  rate  of  absorp- 
tion. That  is  to  say  the  more  rapidly  the  substances  enter  the 
system  from  the  alimentary  tract,  the  greater  the  effect  they 
would  be  likely  to  produce,  assuming  that  their  action  obeys 
the  Mass  Law  for  the  effect  of  concentration  of  one  constituent 
upon  the  speed  of  a given  reaction.  In  accord  with  this  view 
it  must  oe  borne  in  mind  that  the  corn  syrup  fed  contained  con- 
siderable dextrin  which  would  probably  require  some  further  di- 
gestion, while  honey  being  formed  chiefly  of  monosaccharides 
would  De  immediately  absorbed. 

Tne  objection  of  course  may  be  raised  that  there  is  scarce- 
ly enough  difference  in  digestion  periods  of  these  various  types 
of  foodstuffs,  to  account  for  the  difference  in  effect.  However, 
very  slight  differences  in  time  are  all  that  are  required  to 
explain  the  observed  differences  in  uric  acid  excretion. 

It  is  oi  importance  to  notice  the  quantitative  relations 
that  have  been  brought  out  in  this  study.  Host  foodstuffs  exert 


-16- 


some  specific  dynamic  action,  proteins  and  amino-acids  being  by 
far  the  most  pronounced  in  their  influence,  while  fats  and  carbo- 
hydrates have  much  less  effect.  Similarly  10  g of  amino-acids 
caused  a marked  increase  in  uric  acid  excretion,  200  g or  more 
of  carbohyd rates  a somewhat  weakened  effect,  while  200  g of  fat 
had  no  noticeable  action  at  all.  The  objection  exists,  it  must 
be  admitted,  that  fats  which  do  not  affect  uric  acidelimination 
have  more  of  a specific  dynamic  action  than  carbohydrates,  which 
have  beeti  shown  to  cause  a rise  in  uric  acid  excretion.  It  is 
deemed  interesting  and  probably  of  some  significance  however  to 
call  attention  to  the  rough  correlation  existing  between  specific 
dynamic  action  and  influence  on  endogenous  metabolism.  Further— 
more  it  is  to  be  particularly  noted  that  the  types  of  foodstuffs 
other  than  proteins  and  protein  derivatives  exert  an  influence 
on  the  uric  acid  elimination  only  when  very  large  quantities  are 
consumed,  that  is  when  the  organism  is  essentially  overwhelmed 
bjr  the  absorbed  substances* 

It  would  seem  therefore  as  a result  of  the  work  presented 
in  this  paper,  and  from  previous  work  done  in  this  laboratory 
and  elsewhere  that  is  quite  probable  that  one  of  the  factors,  at 
least>  in  the  rise  of  uric  acid  excretion  following  the  ingestion 
of  various  purine-free  foodstuffs,  is  due  to  a general  stimula- 
ting action  upon  cellular  metabolism  and  consequently  upon  nu- 
clear catabolism,  of  digestive  or  catabolic  products  of  the  in- 
gested substances. 


. 


I ..  1.  > 1 


1 


.. 


-17- 


table  i 

Normal  Controls 
No  Food  Ingested 


it 

Experiment  1 


Experiment  3 


Hour 

Vol 

U.A. 

Kr 

Vol 

U.A. 

iCr 

7-8 

70 

32.0 

56.5 

310 

27.8 

62,7 

8-9 

400 

33.8 

77*5 

660 

32.7 

73*7 

9-10 

290 

29.7 

70.0 

310 

32.3 

71.7 

10-11 

150 

29.6 

61.5 

160 

24.9 

56.5 

11-12 

210 

28.6 

76.5 

120 

27.0 

76.4 

it 

it 

Experiment  9 

Experiment,  15 

Hour 

Vol 

U.A. 

Kr 

Vol 

U.A. 

Kr 

7-8 

230 

31*4 

64.8 

160 

31.2 

60.6 

8-9 

400 

33-4 

68.7 

400 

34.3 

69  »2 

9-10 

263 

32.9 

68.2 

285 

31.6 

62.8 

10-11 

100 

31.0 

64.2 

250 

27.3 

65  »6 

11-12 

30 

26.9 

68*2 

70 

24.6 

64.8 

* 

Experiment  20 

Experiment  31 

Hour 

Vol 

U.A. 

Kr 

Vol 

U.A. 

Kr 

► 

7-8 

305 

28.8 

66.6 

70 

22.7 

66 .8 

8-9 

325 

28.7  - 

62.8 

325 

22.0 

69*2 

9-10 

265 

28*9 

66.2 

233 

24,1 

70.5 

10-11 

70 

26.6 

62.6 

210 

22.5 

69.2 

11-12 

70 

22.2 

66.5 

290 

23.4 

65.0 

^Exp  % 

1,  0$t. 

-.4  1921:  Exp. 

2i;  1921: 

Oct.  26 

r»c.  7, 

, 1921: 
1 1921: 

EXP. 

Jan.  11 .2f 
Mar » l > ..'I 


-18- 


TABLE  II 

Influence  of  Glycocoll 
10  g of  glycocollat  9 o’clock 

it 

Experiment  V 


Hour 

Vol 

U.A. 

Kr 

7-8 

45 

23.0 

63.O 

8-9 

260 

28.8 

69*3 

9-10 

95 

45.0 

67*4 

10-11 

360 

48  *2 

68.2 

11-12 

175 

33*6 

66.8 

12-1 

80 

28.6 

65*5 

* October  28,  1921 


-19- 


TAELE  III 
Influence  of  Eats 


Experiment  4 Experiment  6 


Hour 

Vol 

U.  A. 

Kr 

Vol 

U.A. 

Kr 

7-8 

250 

36.2 

60.8 

275 

35*7 

6I.3 

8-9 

429 

34.5 

42.5 

350 

35.5 

65*8 

9-10 

295 

49.2 

770 

60 

33-7 

68.7 

10-11 

170 

29*8 

54*5 

225 

28.6 

64.4 

11-12 

90 

33*5 

62.5 

265 

28.6 

66.2 

12-1 

1?0 

26.8 

62.3 

220 

28.5 

68.2 

it 

Experiment  14 

* 

Experiment  25 

Hour 

Vol 

U,  A. 

Kr 

Vol 

U.A. 

Kr 

6-7 

249 

32.8 

72.3 

93 

26.9 

76.3 

7-8 

595 

350 

65.2 

63 

18.5 

67.5 

8-9 

100 

35  • 0 

75.0 

96 

24.0 

82.0 

9-10 

260 

36.1 

71.3 

60 

26.4 

62.3 

10-11 

88 

24.9 

65.4 

62 

19.8 

75.5 

11-12 

149 

23.8 

64.2 

88 

20.1 

69.8 

12-1 

90 

270 

69*2 

165 

18.3 

66 .2 

1-2 

- 

- 

- 

61 

19.1 

75  * 0 

^Exp.  4,  100  g of  butter  at  9 o’clock,  Oct.  26,  1921 

6,  1/2  pt.  of  whipping  cream  at  8 o'clock,  Kov.  2,  1921 
14,  1 pt . " " " 11  7 " Dec.,  2,  1921 

29,  1 « " " " " 7 M Jan.,  29,  1922 


..  -■  . 


-2  CI- 


TABLE IV 

Influence  of  GlycocollFollowing  Pat  Ingestion.. 

* 

Exp er intent  28 


Hour 

Vol 

U.A. 

Kr 

7-8 

63 

24.2 

68.4 

8-9 

210 

23  V 7 

68.2 

9-10 

205 

22.5 

65*0 

10-11 

130 

23.1 

66.8 

11-12 

77 

26.4 

66 . 8 

12-1 

255 

30.1 

70.0 

1-2 

73 

23.8 

65*2 

2-3 

60 

20.0 

63*8 

1 pt.  of  cream  at  8 o’clock  and  10  g of  glyeo  cdl  at  11  o’cloc 


i 


L.-, 


•21- 


TABLE  V 

Influence  of  Glycerol 

it  it 


Experiment  26 

Experiment 

27 

Hour 

Vol 

U.A. 

Hr 

Vol 

U.A. 

Kr 

7-8 

390 

33*9 

66,7 

95 

21.6 

56*8 

8-9 

155 

29.9 

5O.5 

160 

35*3 

55*0 

9-10 

93 

41.5 

59*4 

77 

39.6 

52.7 

10-11 

80 

37*1 

55*5 

28 

25.6 

53*7 

11-12 

190 

29*9 

58.9 

135 

27.2 

58.2 

12-1 

195  22.1 

u. 

Experiment  3° 

61.2 

330  21.2 

Experiment 

54.3 

it 

32 

Hour 

Vol 

U.A. 

Kr 

Vol 

U.A. 

Kr 

7-8 

72 

26.7 

65.5 

135 

21.2 

67*5 

8-9 

255 

29*5 

63*8 

140 

21.2 

65-7 

9-10 

100 

39.6 

60.7 

82 

31*5 

65*2 

10-11 

72 

30.0 

60.0 

73 

34.2 

69.3 

11-12 

250 

25*9 

60.6 

60 

25.8 

66.7 

12-1 

225 

Exper 

23.1 

it 

iment  33 

65  *4 

320 

22.2 

65.9 

Hour 

Vol 

U.A. 

Kr 

7-8 

290 

23*9 

65.9 

8-9 

32  0 

28.9 

67.5 

9-10 

74 

24.1 

58.7 

10-11 

220 

23.6 

67.2 

11-12 

235 

22.1 

60.2 

12-1  55 

*Exp.  26  50  £ 
2?  50  § 
36  50  g 

22.3 

gl3rcerol  8 

U j 

•<  8 

58.5 

0 * clock 

w 

11 

I^Ii 

2/28/22 

: Exp.  32 
. Exp. 33 

55 

0 • 
10 

0 ' 

g glycerol 
clock  3/7/22 
g glycerol 
clock  5/8/22 

I 


I 


,1 


Kour 

7- 8 

8- 9 

9- 10 

10-11 

11-12 

12-1 

Hour 

7- 8 

8- 9 

9- io 

10-11 

11-12 

12-1 


*Exp 


-22- 


TABLE  VI 


Influence 


Experiment  7 

Vol 

U.A. 

Kr 

145 

31.2 

57*2 

205 

29.3 

68.8 

80 

34.3 

62.7 

92 

32.1 

69.7 

450 

35.5 

66.5 

150 

31.8 

59*1 

it 

Experiment  19 

Vol 

U.A. 

Kr 

125 

34.1 

64  • 8 

155 

25.8 

61.7 

110 

29.8 

62 » 0 

295 

36.9 

65*3 

32  0 

33*5 

64.0 

185 

28.9 

62.2 

f Honey 

Experiment  8 


Vol 

U.A. 

Kr 

160 

32.9 

63*6 

270 

32.7 

70.5 

110 

36,8 

70.0 

325 

36.1 

60.5 

240 

40.8 

69*8 

105 

34.6 

68 . 0 

A 

Experiment  21 

Vol 

U.A. 

Kr 

220 

28.6 

76.5 

24S 

24.6 

74.1 

270 

31.2 

75*2 

225 

35*7 

71.2 

59 

K\ 

CO 

CJ 

73*2 

225 

26.7 

76.8 

7, 

215 

g honey 

at 

8 

0 ' clock, 

Nov.  4,  1921 

8, 

200 

e " 

1* 

8 

1! 

" 9,  1921 

19, 

180 

g " 

8 

1) 

Dfic.  21,  1921 

21, 

12  0 

O’ 

0 

h 

8 

It 

Jan.  13,  1922 

!•  lest  for  sugar  by  Benedict's  solution 


-23- 

table  V I - c o nt  i nu  e d 


4t 

Experiment  22 

Experiment  23 

Hour 

Vol 

U.  A. 

Kr 

Vol 

U.A.  Kr 

7-8 

350 

23*7 

65.7 

480 

29*3  64.3 

8-9 

170 

22.2 

70.9 

210 

25.1  71*0 

9-10 

245 

25*7 

68.5 

125 

27.O  69*5 

10-11 

345 

27.1 

64.6 

225 

31*3  73*2 

11-12 

125 

24.6 

68.5 

315 

27*8  63.0 

12-1 

205 

23*5 

66  .2 

265 

22.6  64.3 

jt 

Experiment  24 

Hour 

Vol 

U.  A. 

Kr 

7-8 

375 

22.6 

71*2 

8-9 

58 

27*7 

69*5 

1 

M 

O 

150 

24.2 

70.4 

10-11 

290 

35*4 

72.5 

11-12 

350 

34.5 

61.7 

12-1 

275 

30.5 

72.5 

* Exp . 

22,  110 
23,  200 
24,  200 

g honey 
? " 

8 " 

0 

00  0000 

-P  S = 

aJ 

'clock  Jan 

tt  ti 

m »» 

. , 18,  1922. 
20,  1922 
24,  1922 

1*  Benedict’s  test  for  sugar 


I 


.1 


-24- 


TABLE  VII 

Influence  of  Karo  Corn  Syrup 


& * 


Experiment  1C 

Experiment 

11 

Hour 

Vol 

U.A. 

Kr 

Vol 

U.A. 

Kr 

7-8 

260 

34.6 

60.7 

60 

28.5 

52.3 

8-9 

370 

31.1 

67.2 

185 

30,6 

74.2 

9-10 

215 

32.2 

72.6 

235 

44.2 

74. 21 

10-11 

300 

29*8 

66.7 

105 

31*3 

67. 81 

11-12 

170 

26.7 

67.4 

50 

27.4 

70.2 

12-1 

165 

25.4 

690 

300 

27.2 

69*2 

& 

it 

Experiment  12 

Experiment 

- 13 

Hour 

Vol 

U.A. 

Kr 

Vol 

U.A. 

Kr 

7-8 

375 

31*9 

70.7 

330 

39.6 

67-7 

8-9 

260 

34.0 

71*3 

225 

39-6 

66.6 

9-10 

115 

34.3 

69. 51 

175 

33*1 

71-3 

10-11 

35 

40.3 

69  • 7 1 

75 

27*3 

66.3 

11-12 

35 

24.2 

65  * 8 

205 

29.0 

69*8 

12-1 

320 

26.2 

70.8 

95 

23.0 

59.5 

it  Exp.  10, 

1Toy. 

16, 

1921, 

200 

S 

at 

8 o’clock 

11, 

18, 

1921 

310 

e 

at 

8 ” 

12, 

1) 

23, 

1921 

320 

s 

at 

8 M 

13, 

30, 

1921 

200 

s 

at 

1.  Benedict’s  test  for  sugar 


. ' \ 


-25- 


TABLE  Vll-eontinued 

u.  A 


Experiment  16 

Experiment 

17 

Hour 

Vol 

U.A. 

Kr 

Vol 

U.A. 

Kr 

7-8 

330 

51.0 

78.6 

260 

35-4 

66.7 

8-9 

130 

50.1 

62.1 

255 

31-5 

71.6 

9-10 

125 

34,8 

70.0 

170 

30.6 

72.6 

10-11 

240 

38»8 

70,8 

310 

32.0 

69-8 

11-12 

390 

29.4 

58.0 

160 

29*2 

6?. 2 

12-1 

73 

31.8 

61.5 

200 

26.1 

69-5 

Experiment  18 

Hour 

Vol 

U»  A» 

Kr. 

7-8 

250 

35.2 

67.6 

8-9 

315 

31.6 

67-0 

9-10 

145 

35-4 

71-5 

10-11 

325 

32.3 

69  -6 

11-12 

325 

29-9 

66.2 

12-1 

155 

35-0 

75*0 

* Exp . 

16,  190 

17,  125 

18,  200 

g Karo 
S 

z " 

at  8 
" 8 
•'  8 

o’clock,  Eec . 9j  1921 
« « 14,  1921 

" " 16,  1921 

'I 


I 


-26- 


TABLE  VIII 

Influence  of  Cystine 

4t 

Experiment  29 


Hour 

Vol 

U.A. 

Kr 

7-8 

105 

26.1 

60.5 

8-9 

125 

26.5 

66 . 5 

9-10 

150 

28.5 

64.9 

10-11 

150 

28.5 

60.2 

11-12 

195 

28.1 

66.8 

12-1 

135 

19.7 

57.2 

it  March  8,  1922*  5 g at  8 o’clock 


I 


SUMMARY 

I The  ingestion  of  glycoc oil  caused  an  increase  in  endo- 
genous uric  acid  excreted. 

IT  Fats  had  no  apparent  effect  on  the  elimination  of  uric 
ac  id » 

III  Previous  feeding  of  fat  had  no  influence  on  the  effect 
produced  by  a subsequent  ingestion  of  glycoc oil* 

IV  The  administration  of  glycerol  caused  an  increase  in 
uric  acid  excretion. 

V  The  eating  of  honey  in  quantities  of  100  g or  more 
caused  an  increase  in  uric  acid  excretion.. 

VI  While  the  consumption  of  small  amounts  of  Karo  corn 
syrup  caused  no  apparent  change  laaiger  amounts  caused  a notice- 
able increase  in  the  elimination  of  uric  acid. 

VII  The  ingestion  of  5 g of  cystine  caused  a slight  rise 
in  uric  acid  excretion.. 


-28- 


BIBLIOGRAPHY 

1.  Scheele,  Opuscu'lar,  1776,  II,  73*  Cited  by  Benedict,  S.  R«, 

J.  Lab.  and  Clin.  Med.,  1916-17,  II,  1* 

2.  Pearson,  Phil.  Tr.  Roy.  Soc.,  London  1793,  15,  Cited  as  (1)* 

3.  Kossel,  A.,  Zeit.  Physiol.  Chem.,  1879,  HI,  284. 

4.  Burian,  R.,  and  Schuy,H.,  Arch.  ges.  Physiol.,  1901,  LXXXVII, 
239;  Zeit.  Physiol.  Chem.,  1904-5,  XLVII,  532?  Arch.  ges. 
Phys.,  1900,  LXXX,  308. 

5.  Siven,  Skand,  Arch.  Physiol.,  1900,  XI,  123* 

6.  Mares,  Aren.  ges.  Physiol.,  1910,  CXXXIV,  59* 

7.  Smetanka,  Arch.  ges.  Physiol.,  1911,  CXXXVIII,  217. 

8.  Mendel,  L.  B.,  and  Stehle,  R.  L. , J.  Biol.  Chem.,  1915,  XXII, 
215. 

9.  Graham,  G.,  and  Ppulton,  E.  P.,  Quart.  J.  Med.,  1913-14,  VII, 
13*  Cited  by  (14). 

10.  Ackero3rd,  H.,  and  Hopkins,  E.  G.,  Biochera.  -J.,  1916,  X,  551* 

11.  Harding,  V.  J.,  and  Young,  E.  G.,  J.  Biol.  Chem.,  1919,  XL, 

227* 

12.  Lewis,  H.  B.,  Dunn,  Id.  S.,  and  Doisy,  E.  A.,  J.  Biol.  Chem., 
1913,  XXXVI,  9* 

13.  Knoop,  E.,  and  Windaus,  A.,  Beit.  Chem.  Phys.  u.  Path.,  1905, 
VI,  392. 

14.  Rose,  W.  C.,  J.  Biol.  Chem.,  1921,  XLVIII,  563. 

15* Heuwirth,  I.,  J.  Biol.  Chem.,  1917,  XXIX,  477, 

16.  Hermann,  A.,  Deutsch.  Arch.  Klin.  Med.,  1888,  XLIII,  273. 

Cited  in  (8). 

17*  Horbaczewski,  J.,  and  Kanera,  E. , Monatsch.  Chem.,  1886,  VII, 
105. 

18.  Umeda,  N.,  Biochem.  .1.,  1915,  IX,  421. 

19.  Lewis,  H.  E . , and  Doisy,  E.  A.,  J . Biol.  Chem.,  1918,  XXXVI,  1 


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